It is believed that elimination of hypoxic protection of human tumors significantly increases the probability of achieving complete tumor cure by radiotherapy. Recently the applicants have realized that heating rodent tumors in the 40-42oC range can cause significant increase in tumor oxygenation, most likely by increasing blood flow. It is hypothesized that i) modest temperature hyperthermia (MTH) is clinically useful in improving oxygenation in tumors., and ii) that the combination of MTH(increase blood flow) with carbogen breathing (increase O2 content in blood) may effectively increase tumor oxygenation. The combination of MTH with other agents which increase tumor blood flow, such as nicotinamide and pentoxyphylline, may also be potentially useful means to increase tumor oxygenation. The goal of this investigation is to reveal the efficacy of MTH at 40.5-42.5oC alone or in combination with the other agents in increasing tumor oxygenation and increasing the response of tumors to radiotherapy. This would be significant since these temperatures are easily achievable in the clinic. FSaII tumors of C3H mice, SCK tumors of A/J mice and R3230 A C tumors of Fischer rats will be used. The tumor oxygenation status will be assessed from pO2 values determined with the Eppendorf pO2 Histograph, hypoxic cell fractions in the tumors with the paired radiation cell survival curve method, and an immunohistochemical method using a fluorinated etanidazole analog (EF5). The response of the tumor to treatment will be assessed from the tumor growth delay and tumor cure (TCD50). From the increase in tumor response and the increase in damage in normal tissue (foot), the therapeutic value of MTH alone or in combination with other agents will be assessed.